Canine animals, e.g. dogs, are affected by various metabolic disorders. A number of metabolic disorders are known in canine animals, including hyperglycaemia, insulin resistance, diabetes, hepatic lipidosis, obesity, hyperinsulinaemia, impaired glucose tolerance, ketosis (in particular ketoacidosis), dyslipidaemia, dysadipokinemia, subclinical inflammation or systemic inflammation, in particular low grade systemic inflammation, which also comprises adipose tissue, Syndrome X (metabolic syndrome) and/or inflammation of the pancreas. Various correlations exist amongst these disorders. Among these disorders, in the dog, diabetes, in particular pre-diabetes and insulin dependent diabetes mellitus, as well as hyperglycaemia, insulin resistance and obesity are gaining more and more importance. This can at least partially be ascribed to changing living and feeding behaviour and that companion animals are living longer due to improved preventive veterinary care during the last years.
Diabetes mellitus is characterized by disturbances in carbohydrate, protein and triglyceride metabolism based on a relative or absolute lack of insulin.
It is a relatively common endocrinopathy in canine animals like the dog. The incidence for diabetes in dogs has increased in the last decades to approximately up to 1.0%. Several risk factors have been identified: age, obesity, neutering, gender and breed.
The current classification divides diabetes mellitus in humans into three classes:
(1.) Type 1 which results from the loss of function of insulin secreting cells, e.g. by immunologic destruction of beta cells or insulin auto-antibodies (juvenile diabetes in humans);
(2.) Type 2 which results from a failure of the insulin stimulated cells to respond properly to insulin stimuli; it is also associated to e.g. amyloid accumulation in beta cells; type 2 usually develops during a long time of the so called pre-diabetes state;(3.) secondary diabetes mellitus which can due to diabetogenic drugs (e.g. long-acting glucosteroids, megestrol acetat, etc.) or to other primary diseases like pancreatitis, pancreas adenocarcinoma, cushing, hypo- or hyperthyroidism, growth-hormone producing tumors resulting in acromegaly.
Canine diabetes is not easily classified, although there are clear similarities and differences between the human and canine diseases. There is no evidence of a canine equivalent to type 2 diabetes, despite obesity being as much a problem in pet dogs as it is in their owners.
The disease can be broadly divided into insulin deficiency diabetes and insulin resistance diabetes (Catchpole et al., Diabetologia 2005. 48: 1948-1956). Insulin deficiency is the most common type. In contrast to the human situation it is not commonly found in young dogs, but rather has possibly similarities to the latent/late autoimmune diabetes of the adult (LADA) form of type 1 diabetes in man, which is characterised by progressive beta cell destruction by autoimmune reactions.
Autoimmunity in dogs is however controversial. As antibodies have been detected only in a subset of dogs with canine diabetes and are discussed to be a consequence rather than a cause of the disease (Catchpole et al., Diabetologia 2005. 48: 1948-1956).
Additionally, in intact female dogs a dioestrus/gestational dependent insulin resistance diabetes is frequent.
For the treatment of diabetes in humans, especially of type 2 diabetes mellitus, several oral antihyperglycaemic drugs are approved. These drugs act, e.g. by stimulating pancreatic insulin secretion in a glucose-independent or glucose-dependent manner (sulfonylurea/meglitinidcs, or DPP IV inhibitors, respectively), by enhancing tissue sensitivity to insulin (biguanides, thiazolidinediones), or by slowing postprandial intestinal glucose absorption (alpha-glucosidase inhibitors).
Some oral antihyperglycaemic drugs have been employed, but are either not effective in diabetic dogs e.g. sulfonylurea drugs or did show some effects on glycemic control, but are unfavorable due to high prevalence of adverse effects e.g. alpha-glucosidase inhibitors (Nelson et al. J small Anim Pract 2000, 41, 486-490).
Other approaches have been contemplated for treating diabetes and reduce hyperglycemia, including inhibition of the renal sodium-dependent glucose co-transporter SGLT2. SGLT2 in the kidney regulates glucose levels by mediating the reabsorption of glucose back into the plasma following filtration of the blood. SGLT2 inhibition thus induces glycosuria and may reduce blood glucose levels. For example, compound 1-cyano-2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzene is described as an SGLT2 inhibitor in WO 2007/128749. A large variety of further SGLT2 inhibitors are also known. In WO 2011/117295, which is concerned with the medication of predominantly carnivorous non-human animals with dipeptidyl peptidase IV (DPP-IV) inhibitors, various SGLT2 inhibitors are recited amongst numerous other types of compounds in the context of combination therapies with DPP-IV inhibitors.
SGLT2 inhibition has not previously been contemplated for treatment of metabolic disorders in canine animals, such as dogs. In canine animals, medications for metabolic disorders are far less advanced than in humans. Unfortunately, even if a treatment or prophylaxis is effective in humans, e.g., or other non-canine animals, it is not possible to conclude that the same approach will also be effective, safe and otherwise appropriate in a canine animal, such as a dog.
Canine animals differ significantly from humans or, e.g., other carnivores as cats in respect of their metabolisms.
Consequently, the pathophysiology of canine metabolic disorders, and thus also their responses to medication of such disorders differs from other species.
Dogs display obesity and all characteristics of a metabolic syndrome similar to e.g. humans and also cats. In contrast to these species, in canine animals this syndrome does not progress to a type 2 diabetes. A pathophysiological hallmark of type 2 diabetes in humans as well as in felines—the pancreatic islet amyloid deposition is absent in dogs (Verkest, Vet J, in press doi.org/10.1016/j.tvjl.2013.09.057)
Diabetic complication e.g. vision problems are commonly seen with diabetes mellitus in dogs, but are rarely found in feline animals. Though, retinopathy is frequently detected in human diabetics—in dogs it is rarely found, but vision problems arise from keratopathy and especially cataracts. These are encountered in up to 80% of diabetic dogs (Beam et al. Vet. Ophtalmol. 1999. 2, 169-172)
Optimal glycaemic control has been shown to be crucial to prevent the development or progression of cataracts (Wang et al. J Diabet. Compl. in press, doi:0.1016/j.jdiacomp.2013.11.002)
The gold-standard treatment of diabetic dogs is currently considered to be injection of insulin. However, no single type of insulin is routinely effective in maintaining control of glycaemia, even with twice-daily administration. Even regulated diabetics may eventually reach a point where their blood glucose is no longer controlled and the insulin must be adjusted, whether by dose or type.
Also with strict compliance from the owner control is often poor and secondary problems are common. Many owners find it impossible to achieve acceptable levels of compliance, as synchronization of food intake and insulin injection is impossible in the majority of cases. Ultimately many dogs with diabetes mellitus are euthanized because of the disease.
The factors governing patient and owner compliance are also very different. In dogs, oral administration, e.g., is yet more highly desirable than in humans.
A treatment that would allow better compliance and therefore better glycaemic control than current insulin-based treatments would help to attenuate the progression of the disease and delay or prevent onset of complications in many animals.
No satisfactory treatment is currently available for metabolic disorders such as obesity, insulin resistance, hyperglycaemia, hyperinsulinaemia, impaired glucose tolerance, hepatic lipidosis, dyslipidaentia, dysadipokinemia, subclinical inflammation or systemic inflammation, in particular low grade systemic inflammation, which also comprises adipose tissue, and associated disorders, such as Syndrome X (metabolic syndrome). Furthermore, these metabolic disorders can be associated to or induced by hypo- or hyperthyroidism, hypercortisolism (hyperadrenocorticism, coshing) and/or growth-hormone access (acromegaly). These metabolic disorders might become clinically manifest e.g. by hypertension, cardiomyopathy, renal dysfunction and/or musculoskeletal disorders in canine animals.
Thus, there remains a particular need for effective, safe and otherwise appropriate treatments of metabolic disorders, including diabetes, in canine animals.